Adenosine Receptors in the Kidney

描述(申请人提供)：高血压是心血管疾病的主要危险因素，影响着超过7000万美国人。肾脏通过调节体液容量和最终的外周阻力来设定长期的血压水平。重新引导肾血管阻力和肾小管重吸收不适当增加的新策略解决了持续性高血压的问题。腺苷是肾脏控制液体平衡和肾血管阻力的主要调节器，作用于近端小管和传入小动脉的特定受体。这两个作用部位提供了新颖和灵敏的液体平衡调节，并被用于管理液体量。腺苷，1型和2型受体(A1-AR，A2-AR)在这两个组织中具有相反的作用。激活A1-AR可收缩传入小动脉，促进近端小管对Na+的摄取。激活A2-AR可扩张传入小动脉，抑制近端小管对Na+的摄取。因此，这些作用的平衡在肾功能中起着重要作用，但目前对此知之甚少。本项目将探索在A1-AR缺陷小鼠两种不同的高血压模型中，每个受体在近端小管Na+和液体摄取以及肾小球反馈介导的肾血管阻力设定中的确切作用。具体目的一是验证在盐敏感型高血压时，近端小管上的腺苷-1受体促进钠离子和容量保持的假说，以及腺苷-2受体调节这种影响的假说。近端小管重吸收将通过肾微灌注和回流技术进行测量，并与血压相关。具体目标二将验证这样的假设：在血管紧张素II诱导的高血压期间，传入小动脉和近端小管中的腺苷-1受体增强血压升高。腺苷-2受体作为这些效应的调节器的作用也将被测试。在慢性血管紧张素II输注后高血压的早期和晚期，将通过肾微穿刺术测量近端小管重吸收和管球反馈。此外，还将对比这两种模型的传入小动脉的血管反应性。这些研究的结果将促进我们对腺苷控制肾依赖性血压调节的了解，并确定新的治疗靶点。 公共卫生相关性：高血压是心血管疾病的主要原因，影响着7000多万美国人。预防高血压发展的新疗法将会有很大的好处。这项研究将探索肾脏中一个被低估的调节液体和盐分平衡的系统，并试图将其与血压控制联系起来。设计的实验将提供关于腺苷受体促高血压作用的新信息，这一作用以前一直未被认识到。这项研究可能会导致开发新的药物来治疗特定形式的高血压。

DESCRIPTION (provided by applicant): Hypertension is the major risk factor for cardiovascular diseases and affects over 70 million Americans. The kidney sets the long-term level of blood pressure by regulation of body fluid volume and ultimately peripheral resistance. Novel strategies to redirect the inappropriate increases in renal vascular resistance and tubular reabsorption address the problem of sustained hypertension. Adenosine is a major regulator of renal control of fluid balance and renal vascular resistance, acting on specific receptors in the proximal tubule and in the afferent arteriole. These two sites of action provide novel and sensitive regulation of fluid balance and have been targeted to manage fluid volume. Adenosine, type 1 and type 2 receptors (A1-AR, A2- AR) have opposing actions in both tissues. Activation of A1-AR constricts the afferent arteriole and promotes Na+ uptake in the proximal tubule. Activation of A2-AR dilates the afferent arteriole and inhibits Na+ uptake in the proximal tubule. Therefore the balance of these actions plays an important role in renal function, but is currently poorly understood. This project will explore the precise roles of each receptor in the uptake of proximal tubule Na+ and fluid and on the setting of renal vascular resistance mediated by tubuloglomerular feedback during two distinct models of hypertension in A1-AR deficient mice. Specific Aim one will test the hypothesis that adenosine-1 receptors in the proximal tubule promote Na+ and volume retention during salt- sensitive hypertension and that adenosine-2 receptors modulate that influence. Proximal tubule reabsorption will be measured by renal microperfusion and recollection techniques and correlated to blood pressure. Specific Aim two will test the hypothesis that adenosine-1 receptors in the afferent arteriole and in the proximal tubule enhances blood pressure increase during angiotensin II-induced hypertension. The role of adenosine-2 receptors as modulators of these effects will also be tested. Proximal tubule reabsorption and tubuloglomerular feedback, measured by renal micropuncture techniques, will be assessed during the early and late stages of hypertension after chronic angiotensin II infusion. In addition, vascular reactivity of afferent arterioles will be contrasted between these two models. Results from these studies will advance our knowledge of adenosine control of renal-dependent blood pressure regulation and identify new targets for therapy. PUBLIC HEALTH RELEVANCE: Hypertension is the leading cause of cardiovascular disease, affecting over 70 million Americans. Novel treatments for the prevention of the development of hypertension would have great benefits. This study will explore an under-appreciated system in the kidney that regulates fluid and salt balance, and try to link it to blood pressure control. The designed experiments will provide new information about the pro-hypertensive role of adenosine receptors, which has been previously unrecognized. This study may lead to the development of novel agents to treat specific forms of hypertension.